resistant, wy.pptx

8/6/2019 Resistant, WY.pptx

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Failure and change to second line

Prepared By: Dr. Wut Yi

STO, C&S

BI-MM


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Indications for Switching

Toxicity

New Problem (TB, Pregnant)

Failure

Virologic failure

Immunologic failure

Clinical Failure

Difficulty adhering to the regimen Current antiretroviral regimen is suboptimal


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FDA-Approved Drugs for HIV Therapy

NNRTIs

Delavirdine (DLV)

Efavirenz (EFV)

Nevirapine (NVP)

PIs

Amprenavir (APV) discontinued

2004

Atazanavir (ATV)Darunavir (DRV)

Fosamprenavir (FPV)

Indinavir (IDV)

Lopinavir/ritonavir (LPV/RTV)

Nelfinavir (NFV)

Ritonavir (RTV)Saquinavir (SQV hgc)

Tipranavir (TPV)

Abacavir (ABC)

Didanosine (ddI)

Emtricitabine (FTC)

Lamivudine (3TC)

Stavudine (d4T)Tenofovir (TDF)

Zalcitabine (ddC) withdrawn 2005

Zidovudine (ZDV)

3TC/ABC

3TC/ABC/ZDV

3TC/ZDVFTC/TDF

NRTIs

Fusion Inhibitors (FIs)

Enfuvirtide (ENF)

Maraviroc (CCR5 inhibitor)

Multiple Class

EFV/FTC/TDF

Integrase InhibitorsRaltegravir


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RESPONSE TO TREATMENT

Virological

Immunological

Clinical

Falling and then

undetectable viral load

Rise in CD4 count

(10/month)

Weight gainand rise in Karnofski score

Symptoms, PPE less


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How to detect treatment failure

Asymptomatic withCD4 < 200

(Monitor Adherence)

WHO class III or IV

Clinical monitoringevery month

CD4 every 6 months

Clinical monitoring atleast every month


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How to detect?

Reason for failure1. Treatment failure

no optimal treatment

regimen

non-adherence

bad absorption, druginteractions

Resistance

HIV-2

2. Other reasons

side effects of ARVs or

other drugs

IRIS

OI or other HIV relatedproblems.

Non-HIV relatedproblems


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How to detect?

MonitoringAdherence(Importance

*100000000)

Monitoring Viral Load 6 monthsapart


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How is ART failure defined?

Clinical:

New/recurrent OI or malignancy after

6 months on ARTBeware IRIS

Immunological:

Fall CD4 to pre-treatment level, or

50% fall from peak level, after 6months ART, persistant CD4 countsbelow 100/mm3

CD4 repeated 3 months apart


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How is ART failure defined?

Virological failure

Plasma viral load above 5000 copies/ml in

a person on ART


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Immunogical Success

Increase in CD4 count at 12 weeks: 10-50cells/mm

Increase in CD4 count at 16-32 weeks: 30-50cells/mm

Increase in CD4 count/year: 80-150 cells/mm


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Remember

CD4 counts can vary significantly and donot always predict virological failure

20% with no CD4 increases have undetectable VL(Ukraine 14/15 pts with no significant CD4 hadundetectable VL)

40% with immunological failure have undetectableVL

40-70% of those with virological failure dont have

immunological failure Infection, pregnancy, alcohol, stress

CD4 alone is not a reliable method to

assess effectiveness of ART


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Remember

Despite immunological and virological failure, patients doclinically very well for years

only 1/3 have immunological failure after 3 years of virilogicalfailure if the ART continued

Long-term outcomes on 2nd and 3rd line regimens areinferior to 1st line regimens

1st mean 11 months, 2nd mean 7 months

No FDC, o pill burden, food restrictions, side-effects

Options for 2nd line therapy are limited Registration, cost, cold-chain

rapid changes can quickly use up all ARV options


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Remember

If failure is due to poor adherence, then changing therapywill have no benefit

Always exclude co-existent OI or IRIS

If possible, clinical or immunological failure should alwaysbe confirmed with a viral load measurement of >1000copies/ml prior to changing to a second-line regimen

Failure due to ARV resistance will not occur before 12months of ART for treatment nave patients, and 6months of ART for treatment experienced patients.


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When to Change

Should be a combination of bothclinical and immunological failure

Decision to change to 2nd line made bydoctor in consultation with HIV specialist


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ABC or 3TC (sAZT)#

ddI or TDF

EFV or NVPNRTI sparing option if the triple NRTIapproach were used in first-linetherapy

Standard second-line option if NRTI/NNRTIapproach were used in first-line therapy

Second line ARV drugs in adults and adolescents

PI/r*

* Ritonavir-boosted PIs (ATV/r, FPV/r, IDV/r, LPV/r and SQV/r) are considered as the key component in second-line regimens and its

use should be reserved for this situation. LPV/r is the only PI currently available as a FDC and a new formulation that doesn't need

refrigeration was recently launched. In the absence of a cold chain and where the new LPV/r formulation is not available, NFV can be

employed as the PI component but it is considered less potent than a RTV-boosted PI.

# The use of 3TC (AZT) are listed for strategic use as resistance to both drugs is predicted to be present following failure on the

respective first-line regimen listed. 3TC will maintain the M184V mutation which may potentially decrease viral replicative capacity as

well as induce some degree of viral resensitization to AZT or TDF; AZT may prevent or delay the emergence of the K65R mutation.However, it must be stressed that the clinical efficacy of this strategy in this situation has not been proven.


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ABC or 3TC (sAZT)#

ddI or TDF




PI/r*









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ABC or 3TC (sAZT)#

ddI or TDF




PI/r*









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How can we minimize ART failure?

Do not prescribe ART at the first visit

Financial problem

Follow up regularly

Regimen and dosage(take right time, right dose andreduce pill burden)

Adherence


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AZT

300 mg BID

Side Effects(SE):y Nausea, vomiting,HA, fatigue - common, early

y Later: anemia, leukopenia, GI, myositis, insomnia

y Pigmentation of nail beds, lactic acidosis, fatty Liver

Food Interactions: None with or without food is ok

Food decreases AZT-related nausea

Use non-AZT regimen if initial Hb


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DDI (Didanosine)

Tabs 200 mg BID for wt >/= 60 kg

125 mg BID for wt < 60 kg

If use buffered tablets, 2 or more tablets

must be used at each dose to provideadequate buffer

Tablets must be chewed or dissolved

y Powder--slightly different absorption and doses

y QD dosing: 400 mg/d for >/=60 kg, 250mg


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DDI toxicity

Peripheral Neuropathy

Nausea

Diarrhea, abdominal pain

Pancreatitis Lactic acidosis, fatty liver

Not combined with D4T (combined toxicity)

Not combined with Tenofovir (drug interactions)


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TDF

300 mg (one pill) once daily Nucleotide

eliminates a phosphorylation step foractivation

Reduce dose of DDI if taken concomitantly Side effects (Rare):

nausea/vomiting, diarrhea, anorexia

can be associated with lactic acidosis,

pancreatitis, hepatotoxicity, worsening renalfailure (? genetic)

Resistance Pattern:Slow--Multiple mutations

Activity against Hepatitis B


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Abacavir (ABC)

Dosing: 1 x 300mg tablet BID

Food Interactions: no food interactions

Toxicity

Diarrhea,Nausea, Headache all mild

Lactic acidosis, fatty liver (rare)

Allergic reaction (HSR) : 5%


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ABC

Systemic symptoms: feels sick, fever, malasie

Rash, GI, Respiratory

Peak day around day 11

Symptoms related to doses

Decision to stop because ofHSR isforever. Irrevocable. Therefore make it

wisely. Role of initial education, partnership.

Have patient return any unused ABC.

Future: Genetic Testing for who will havereaction


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FTC

Flourinated 3TC-very similar

Dosing: 1 x 200mg capsule QD

Food Interactions: no food interactions

Activity against Hepatitis B

Toxicity

Mild abdominal discomfort

Occasional nausea

Hyperpigmentation


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Preferred boosted PI

Lopinavir/ritnavir

Atazanavir/ritonavir

( Ritonavir boosted= increase the drug level ofother PI

= increase dosing interval

= slow mutation and slow resistant)


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Kaletra (Lip/r)

Dose: 400/100mg twice daily (Thermostable formulation: 2tablets twice daily; old formulation: 3 tablets twice daily)

Advantages of the thermo-stable formulation: lower pill

burden, no food restriction. Generally well-tolerated Most common adverse effects : nausea and diarrhoea,

increase of hepatic transaminases Class adverse reactions: insulin resistance, fat accumulation

and hyperlipidaemia

can increase the risk of nephrotoxicity with TDF If given with rifampicin need to increase the dose to

533/133mg twice daily, and monitor closely for hepatitis (riskincreased).


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Third line

Darunavir (DRV)

Ritonavir

Raltegravir

Etravirine (ETV)

resistant, wy.pptx

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